This invention relates to methods of treating cyclooxygenase mediated diseases and certain pharmaceutical compositions therefor.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. More recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized initially from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
Such a compound would also be of use in the treatment of Alzheimer's disease and osteoporosis.
A brief description of the potential utility of cyclooxygenase-2 is given in an article by John Vane, Nature, Vol. 367, pp. 215-216, 1994.
U.S. Pat. No. 3,196,162 (Jul. 20, 1965) discloses structures of anti-inflammatory agents which differ from the present compounds most notably by the presence of the 5-methoxy substituent which we have shown to be inferior to the 5-halo analogs of the present invention. WO 93/00334 discloses structures which differ from the present compounds in being 3-indoleacetamides and having no substitution at the 2- and 5-positions. Khim Geterotsikl, Soedin., (1), 100-2, 1969 discloses structures which differ from the present compounds notably by being 3-indolecarboxylic acid. UK patent application 2,225,012 (May 23, 1990) discloses a series of indole-2 (or -3)-alkanoic acid as being anti-thrombotic agents, but which differ from the present compounds by having no substituent on the 1-benzyl group and by having at least 4-carbon atoms in the 2-substituent. Merck Frosst has a series of patents disclosing N-benzylindole alkanoic acids (U.S. Pat. Nos. 5,081,145, 5,202,321 and 5,204,344). However, these differ structurally from the present compounds in that they carry the alkanoic acid in the 2-position rather than the 3-position. The compounds of these Merck Frosst patents are of use as prostaglandin antagonists, inhibitors of leukotriene biosynthesis or as synthetic intermediates.